The Yale-SCOR is bringing together leading basic and clinical science experts to establish an interdisciplinary, translational, cross-species program of research aimed at identifying novel therapeutics to address the critical health disparity that female smokers face. Tobacco use is the leading cause of preventable morbidity and mortality in the United States. Women, compared to men, have poorer rates of smoking cessation, exacerbated health risks, and FDA-approved medications for smoking cessation may not be as effective for women or have emerging limits due to side effects. However, few attempts have been made to develop gender-sensitive smoking cessation treatments. The considerable body of data suggesting that women are more likely to smoke to regulate negative affect and stress while men are more likely to smoke for the reinforcing properties of nicotine suggests an important direction in the development of a new approach to smoking cessation treatments. Using both preclinical and clinical strategies, our interdisciplinary team will probe te noradrenergic system's effects on stress-reactivity and nicotine reinforcement -hypothesizing that (a) different brain systems modulated by noradrenergic activity are activated by smoking in women and men, and (b) guanfacine (an alpha-2a noradrenergic agonist) can preferentially target these gender-sensitive systems to improve smoking cessation outcomes. Using a translational approach with an interdisciplinary team effort, we are proposing three projects that will have inter-related and shared goals, with each providing unique contributions to the development of gender-sensitive therapeutics. This new application will catalyze Yale's significant resources to support interdisciplinary and translational science in women's health to pursue extremely timely scientific findings that could represent a breakthrough in our understanding of treatments for a public health problem that affects millions daily. Our specific aims and objectives of the Yale-SCOR are to: AIM 1: Evaluate the role of the noradrenergic system and its interactions with cholinergic and dopaminergic systems, in stress-induced smoking relapse and nicotine-based reinforcement, and use these findings to inform and expedite the development of gender-sensitive therapeutics for smoking cessation. AIM 2: Mentor junior investigators in conducting interdisciplinary translational research on tobacco use and women's health through training opportunities, including clerkships with SCOR PIs, and pilot funding. AIM 3: Be a national resource to invigorate and galvanize the study of sex and gender differences in relation to smoking by providing expert consultation; supporting faculty training awards; mining national data on gender, smoking and health outcomes to inform health policy; and expanding our current program of local and national community outreach.